ABSTRACT
(1) Background: Sepsis is a life-threatening condition, and most patients with sepsis first present to the emergency department (ED) where early identification of sepsis is challenging due to the unavailability of an effective diagnostic model. (2) Methods: In this retrospective study, patients aged ≥20 years who presented to the ED of an academic hospital with systemic inflammatory response syndrome (SIRS) were included. The SIRS, sequential organ failure assessment (SOFA), and quick SOFA (qSOFA) scores were obtained for all patients. Routine complete blood cell testing in conjugation with the examination of new inflammatory biomarkers, namely monocyte distribution width (MDW), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR), was performed at the ED. Propensity score matching was performed between patients with and without sepsis. Logistic regression was used for constructing models for early sepsis prediction. (3) Results: We included 296 patients with sepsis and 1184 without sepsis. A SIRS score of >2, a SOFA score of >2, and a qSOFA score of >1 showed low sensitivity, moderate specificity, and limited diagnostic accuracy for predicting early sepsis infection (c-statistics of 0.660, 0.576, and 0.536, respectively). MDW > 20, PLR > 9, and PLR > 210 showed higher sensitivity and moderate specificity. When we combined these biomarkers and scoring systems, we observed a significant improvement in diagnostic performance (c-statistics of 0.796 for a SIRS score of >2, 0.761 for a SOFA score of >2, and 0.757 for a qSOFA score of >1); (4) Conclusions: The new biomarkers MDW, NLR, and PLR can be used for the early detection of sepsis in the current sepsis scoring systems.
ABSTRACT
The COVID-19 pandemic has caused significant morbidity and mortality. Currently, there is a critical shortage of proven treatment options and an urgent need to understand the pathogenesis of multi-organ failure and lung damage. Cytokine storm is associated with severe inflammation and organ damage during COVID-19. However, a detailed molecular pathway defining this cytokine storm is lacking, and gaining mechanistic understanding of how SARS-CoV-2 elicits a hyperactive inflammatory response is critical to develop effective therapeutics. Of the multiple inflammatory cytokines produced by innate immune cells during SARS-CoV-2 infection, we found that the combined production of TNF-α and IFN-γ specifically induced inflammatory cell death, PANoptosis, characterized by gasdermin-mediated pyroptosis, caspase-8-mediated apoptosis, and MLKL-mediated necroptosis. Deletion of pyroptosis, apoptosis, or necroptosis mediators individually was not sufficient to protect against cell death. However, cells deficient in both RIPK3 and caspase-8 or RIPK3 and FADD were resistant to this cell death. Mechanistically, the JAK/STAT1/IRF1 axis activated by TNF-α and IFN-γ co-treatment induced iNOS for the production of nitric oxide. Pharmacological and genetic deletion of this pathway inhibited pyroptosis, apoptosis, and necroptosis in macrophages. Moreover, inhibition of PANoptosis protected mice from TNF-α and IFN-γ-induced lethal cytokine shock that mirrors the pathological symptoms of COVID-19. In vivo neutralization of both TNF-α and IFN-γ in multiple disease models associated with cytokine storm showed that this treatment provided substantial protection against not only SARS-CoV-2 infection, but also sepsis, hemophagocytic lymphohistiocytosis, and cytokine shock models, demonstrating the broad physiological relevance of this mechanism. Collectively, our findings suggest that blocking the cytokine-mediated inflammatory cell death signaling pathway identified here may benefit patients with COVID-19 or other cytokine storm-driven syndromes by limiting inflammation and tissue damage. The findings also provide a molecular and mechanistic description for the term cytokine storm. Additionally, these results open new avenues for the treatment of other infectious and autoinflammatory diseases and cancers where TNF-α and IFN-γ synergism play key pathological roles.
ABSTRACT
BACKGROUND: COVID-19 may lead to severe disease, requiring intensive care treatment and challenging the capacity of health care systems. The aim of this study was to compare the ability of commonly used scoring systems for sepsis and pneumonia to predict severe COVID-19 in the emergency department. METHODS: Prospective, observational, single centre study in a secondary/tertiary care hospital in Oslo, Norway. Patients were assessed upon hospital admission using the following scoring systems; quick Sequential Failure Assessment (qSOFA), Systemic Inflammatory Response Syndrome criteria (SIRS), National Early Warning Score 2 (NEWS2), CURB-65 and Pneumonia Severity index (PSI). The ratio of arterial oxygen tension to inspiratory oxygen fraction (P/F-ratio) was also calculated. The area under the receiver operating characteristics curve (AUROC) for each scoring system was calculated, along with sensitivity and specificity for the most commonly used cut-offs. Severe disease was defined as death or treatment in ICU within 14 days. RESULTS: 38 of 175 study participants developed severe disease, 13 (7%) died and 29 (17%) had a stay at an intensive care unit (ICU). NEWS2 displayed an AUROC of 0.80 (95% confidence interval 0.72-0.88), CURB-65 0.75 (0.65-0.84), PSI 0.75 (0.65-0.84), SIRS 0.70 (0.61-0.80) and qSOFA 0.70 (0.61-0.79). NEWS2 was significantly better than SIRS and qSOFA in predicating severe disease, and with a cut-off of5 points, had a sensitivity and specificity of 82% and 60%, respectively. CONCLUSION: NEWS2 predicted severe COVID-19 disease more accurately than SIRS and qSOFA, but not significantly better than CURB65 and PSI. NEWS2 may be a useful screening tool in evaluating COVID-19 patients during hospital admission. TRIAL REGISTRATION: : ClinicalTrials.gov Identifier: NCT04345536. (https://clinicaltrials.gov/ct2/show/NCT04345536).